Suppression of Pathological Spontaneous Cortical Dynamics and Inflammation in NeuroHIV

NeuroHIV 病理性自发皮质动力学和炎症的抑制

• 批准号: 10472343
• 负责人: Tony W Wilson
• 金额: $ 68.87万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472343
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adult; Affect; Agreement; Anti-Inflammatory Agents; Area; Attention; Automobile Driving; Behavior; Behavioral; Brain; Brain Mapping; Brain region; Cannabinoids; Cannabis; Chronic; Cognitive; Complication; Data Analyses; Disease; Economics; Environment; Epidemic; Equation; Exhibits; Foundations; Functional disorder; General Population; Goals; HIV; HIV Infections; Heel; Human; Immune; Impaired cognition; Impairment; Inflammation; Knowledge; Lead; Life Expectancy; Link; Mediating; Methods; Mitochondria; Modeling; Molecular; Motor; Neurologic; Neurophysiology - biologic function; Neuropsychological Tests; Oxidation-Reduction; Participant; Pathologic; Pathway interactions; Performance; Persons; Property; Publishing; Quality of life; Reporting; Request for Proposals; Research; Risk; Sampling; Scientific Advances and Accomplishments; Seminal; Superoxides; System; Systems Biology; Targeted Research; Task Performances; Therapeutic; Unemployment; Viral; Western World; Work; cognitive function; cognitive performance; comorbidity; immune activation; improved; innovation; instrumentation; marijuana use; medication compliance; mild cognitive impairment; molecular marker; nervous system disorder; neuroAIDS; neuroimaging; neuroimaging marker; neuroinflammation; relating to nervous system; virtual

Project Summary/Abstract Persons with HIV (PWH) in the western world have a life expectancy near that of the general population, yet they remain at a significantly elevated risk of developing cognitive impairments. Such impairments are the most common neurological complication of HIV disease, and research targeting these comorbidities is one of four overarching priorities identified by the Office of AIDS Research (NOT-OD-20-018). Recent human neuroimaging studies have broadly shown that the milder impairments more frequently observed in virally-suppressed PWH arise from multiple cortical circuits, which is a major paradigm shift from the putative subcortical origins of the severe cognitive impairments observed earlier in the epidemic. However, despite this progress, we still have a limited understanding of the molecular precursors and pathways that lead to dysfunction in these cortical circuits, and virtually no viable therapeutic options, with only limited potential avenues (e.g., cannabis) on the horizon. This proposal responds to RFA-DA-22-012, which calls for applications that “define HIV-associated persistent inflammation and its causal link to HIV-related comorbidities such as … neurological disorders,” “explore the interaction between HIV immune activation and cannabinoid use as it pertains to neurological disorders,” and “characterize and validate the potential anti-inflammatory, immune stabilizing (beneficial) properties of canna- binoids in chronic HIV infection.” The proposed project responds to this call with an innovative, large-scale, dynamic neuroimaging and molecular markers study that leverages multiple recent discoveries to identify the impact of cannabis use on the mechanisms and pathways underlying HIV-related persistent inflammation and decline in cognitive and brain function in virally-suppressed PWH. Each of our aims builds on a major discovery in 2021. Specifically, Aim 1 examines whether cannabis use modulates the superoxide-sensitive mitochondrial redox environment and neuroinflammation in PWH, which follows on the heels of our finding that mitochondrial function differentially modulates superoxide in PWH compared to controls, and that the latter predicts neuro- inflammation and cognitive function. Aim 2 identifies whether attention- and motor-related neural oscillations are directly modulated by the same superoxide-sensitive pathway in PWH, which builds on our major discovery featured in PNAS that the superoxide-sensitive mitochondrial redox environment predicts cognitive performance and the underlying neural oscillations in controls. Finally, Aim 3 builds on our recent breakthrough that cannabis suppresses the pathological spontaneous cortical activity that is observed in PWH, and further accentuated in cognitively impaired PWH, by examining whether these cannabis-induced alterations are mediated by the superoxide-sensitive mitochondrial redox environment. These recent, major scientific advances provide an ideal foundation to directly address the key objectives of this RFA through an innovative project that utilizes state-of- the-art neuroimaging and systems biology methods, and builds on an established model of neuroinflammation in PWH that has been linked to cognitive and neural function in healthy adults and cognitive decline in PWH.

项目总结/摘要 在西方世界，艾滋病毒感染者（PWH）的预期寿命接近一般人群，但 他们患认知障碍的风险仍然很高。这种损伤是最 HIV疾病的常见神经系统并发症，针对这些并发症的研究是四个之一 艾滋病研究办公室确定的首要优先事项（NOT-OD-20-018）。近期人类神经影像学 研究广泛表明，在病毒受到抑制的PWH中更常见的是轻度损伤 起源于多个皮层回路，这是一个主要的范式转变，从假定的皮层下起源， 在流行病早期观察到的严重认知障碍。然而，尽管取得了这一进展，我们仍然有一个 对导致这些皮层回路功能障碍的分子前体和途径的理解有限， 实际上没有可行的治疗选择，只有有限的潜在途径（例如，大麻在地平线上。 该提案响应RFA-DA-22-012，该提案要求应用程序“定义HIV相关的持续性 炎症及其与艾滋病毒相关合并症的因果关系，如......神经系统疾病，”“探索 艾滋病毒免疫激活和大麻素使用之间的相互作用，因为它涉及神经系统疾病，”和 “表征和验证美人蕉的潜在抗炎，免疫稳定（有益）特性， 在慢性HIV感染中的作用”拟议的项目以一个创新的、大规模的、 动态神经成像和分子标记研究，利用多个最近的发现，以确定 大麻使用对艾滋病毒相关持续性炎症的机制和途径的影响， 病毒抑制PWH患者的认知和脑功能下降。我们的每一个目标都建立在一个重大发现之上 2021年具体来说，目标1检查大麻使用是否调节超氧化物敏感的线粒体 PWH中的氧化还原环境和神经炎症，这是继我们发现线粒体 功能差异调节超氧化物在PWH相比，控制，后者预测神经， 炎症和认知功能。目的2确定是否注意力和运动相关的神经振荡 直接由PWH中相同的超氧化物敏感途径调节，这建立在我们的重大发现基础上。 在PNAS中，超氧化物敏感的线粒体氧化还原环境预测了认知能力。 和控制中潜在的神经振荡。最后，目标3建立在我们最近的突破基础上， 抑制在PWH中观察到的病理性自发皮质活动，并在PWH中进一步加重 认知受损的PWH，通过检查这些大麻诱导的改变是否由 超氧化物敏感的线粒体氧化还原环境。这些最新的重大科学进展提供了一个理想的 基金会通过一个创新项目直接解决这一RFA的关键目标， 最先进的神经影像学和系统生物学方法，并建立在神经炎症的既定模型 在PWH中，它与健康成人的认知和神经功能以及PWH的认知下降有关。